CD52 is a glycosylated, glycosylphosphatidylinositol (GPI)-anchored cell surface protein found in abundance on a variety of normal and malignant lymphoid cells especially B and T cells (Gilleece et al, Blood 82 807-812 (1993); Hale et al, J Biol Regul Homeost Agents, 15 p386- 391 (2001); Rodig et al, Clin Cancer Res 12, p7174-7179 (2006)). CD52 is expressed at lower levels on myeloid cells such as monocytes, macrophages and dendritic cells (DC) with little expression found on mature natural killer (NK) cells, neutrophils, and hematological stem cells. CD52 is also produced by epithelial cells in the epididymis and duct deferens, and is acquired by sperm during passage through the genital tract (Hale et al, ibid,; Domagala et al, Med Sci Monit 7 p325-331 (2001)). The exact biological function of CD52 remains unclear but some evidence suggests that it may be involved in T cell migration and co-stimulation (Masuyama et al, J Exp Med 189 979-989 (1999); Watanabe et al, Clin Immunol 120 247-259 (2006)).
Campath-1H (alemtuzumab, Campath®, MabCampath®) is a humanised anti-human CD52 monoclonal antibody that exhibits potent in vitro antibody-dependent cell mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). CD52 is present on at least 95% of all human peripheral blood lymphocytes and monocytes/macrophages (Hale G. et al., The CAMPATH-1 antigen (CD52). Tissue Antigens 1990, 35:118-127). Campath-1H recognizes an epitope which consists of the carboxy terminal four amino acids of the mature CD52 protein and a portion of the negatively charged GPI anchor. Due to its significant cytotoxic effects, Campath-1H is capable of depleting CD52 positive cells in vivo and it is approved for front line and third line treatment of chronic lymphocytic leukemia (CLL). Campath-1H has been evaluated for its utility in the treatment of several autoimmune diseases, including rheumatoid arthritis, vasculitis, myositis, Wegener's disease and diabetes. The most advanced studies of Campath-1H are in treating relapsing remitting multiple sclerosis (MS). These studies showed a significant improvement in time to relapse compared to human interferon beta-1a (Rebif® (i e, interferon beta-Ia)).
A major limitation of Campath-1H is immunogenicity whereby antibodies are induced in up to 70% of patients (Therapeutic Monoclonal Antibodies: From Bench to Clinic, ed. Zhiqiang An (2009) ISBN: 978-0-470-11791-0). In order to improve the clinical utility of anti-CD52 antibodies, there is a major need for improved anti-CD52 antibodies which are not associated with significant immunogenicity in patients.